Inflammation is associated with tissue trauma, peritonitis, colitis, enteritis, vasculitis, pulmonary emphysema, cystic fibrosis, chronic pulmonary infection, bronchitis, psoriasis, arthritis, rheumatoid arthritis, allergic contact dermatitis, atopic dermatitis, glomerulonephritis, ARDS, pancreatitis and sepsis, among other inflammatory states (reviewed in Weiss, S. J. N. Engl. J. Med. 320, 365, (1989); Lehrer, R. I. et al. Ann. Intern. Med. 109, 127 (1988); Malech, H. L. et al. Ann. Intern. Med. 317, 687, (1987)). The chemotaxis and accumulation of neutrophils (i.e., neutrophil diapedesis), as well as the release of antibiotic proteins (e.g., defensins), proteolytic enzymes (e.g., serprocidins), and granule-based toxins are associated with inflammation (reviewed in Syntex Research Canada Annual Reports in Med. Chem. 28, 187-195 (1993)). The unmodulated activity of proteolytic enzymes, and neutrophil diapedesis are important causes of inflammation.
The serprocidins include serine proteinases such as human leukocyte elastase (i.e. HLE), cathepsin G (i.e. Cath G) and proteinase 3 (i.e. PR-3). Inflammation can be reduced by the presence of biological inhibitors such as alpha-1-proteinase inhibitor, secretory leukocyte protease inhibitor, and elafin. Synthetic agents capable of reducing serine protease activity are of therapeutic value as anti-inflammation drugs (Snider, Drug. Dev. Res. 10:235-253, 1987; Wewers et al., New Engl. J. Med. 316:1055-1062, 1987; McElvaney et al., Lancet 337:392-394, 1991; McElvaney et al., Am. Rev. Resp. Dis. 145(4)part 2, suppl.; Weinbaum et al., In Focus on Pulmonary Pharmacology and Toxicology, Hollinger, ed., CRC Press, Boca Raton, Fla., 1991; Krantz in Ann. Rep. Med. Chem., Bristol, ed., Vol. 28, pp. 187-195, Academic Press, Inc., San Diego, Calif., 1993). Examples of compounds that have been used to inhibit serine proteinases include derivatives of isocoumarin and cephalosporin (Hernandez et al., J. Med. Chem. 35:1121-1129, 1993; Knight et al., Biochemistry 31:4980-4986, 1992) haloenol lactones (Rai et al., J. Med. Chem. 35:4150-4159, 1992), substituted succinimides and related compounds (Groutas et al., J. Med. Chem. 32:1607-1611, 1989; Groutas et al., J. Am. Chem. Soc. 111: 1931-1932, 1989; Groutas et al., J. Enzyme Inhibition 3:237-243, 1990; Groutas et al., BioMed. Chem. Lett. 2:1565-1570, 1992), ynenol lactones (Copp et al., Biochemistry 7:169-178, 1987), and derivatives of saccharin (Groutas, W. C. et al. Bioorg. & Med. Chem. 1(4) 273-277 (1993); Groutas et al. J. Med. Chem. 36, 3178-3181 (1993).